Jacob Laubach, MD, Paul Richardson, MD, Nikhil Munshi, MD, and Kenneth Anderson, MD
Drs. Richardson, Munshi, and Anderson
are advisory board members for Celgene and Millennium. Dr. Munshi also consults
for Celgene and Millennium.
The authors are all in the Department
of Medicine at Harvard Medical School and Dana-Farber Cancer Institute. Dr.
Laubach is Instructor in Medicine, and Dr. Richardson is Associate Professor
and Clinical Director, Jerome Lipper Center for Multiple Myeloma. Dr. Munshi is
Associate Professor and Associate Director, Jerome Lipper Center for Multiple
Myeloma, and Dr. Anderson is Kraft Family Professor of Medicine and Director,
Jerome Lipper Multiple Myeloma Center.
High-dose therapy with autologous stem
cell transplantation (ASCT) has played a central role in multiple myeloma (MM)
therapy since the approach was first introduced by McElwain and colleagues in
1983.1 ASCT was initially most often utilized in the management of relapsed and
refractory disease, wherein it provided a means to overcome drug resistance
through dose intensification. Although brief, significant responses were
observed in this setting. ASCT was subsequently evaluated in newly diagnosed MM
patients following induction therapy. In a pivotal trial comparing standard-dose
chemotherapy to standard-dose therapy followed by ASCT, the incorporation of
ASCT improved overall response, complete response, event-free survival, and
overall survival.2 Subsequent clinical trials comparing conventional therapy to
ASCT yielded conflicting results, as some demonstrated improvement in
event-free and overall survival associated with ASCT patients, while others did
not. Comparison of single versus tandem ASCT showed benefit of a second transplant
limited to those who did not achieve at least a very good partial response after
the first and to patients with otherwise favorable disease characteristics,
such as normal cytogenetics and low β2-microglobulin.3 With respect to timing,
early ASCT following induction therapy is associated with improvement in
event-free survival relative to delayed transplant at time of relapse, but not
with improvement in overall survival.4
ASCT has traditionally been undertaken
with caution in the context of high-risk disease as defined by cytogenetic abnormalities
such as translocation (t)(4;14), due to shortened time-to-progression and
overall survival post-transplant in this population. Outcomes with ASCT are
best among individuals who achieve maximal reduction in tumor burden, and
multiple studies have shown that complete response following ASCT is associated
with prolonged event-free survival and overall survival. It would thus appear that
the benefit of ASCT in MM derives from its ability to induce deeper responses
through dose intensification and thereby suppress the tumor clone for an extended
The Impact of
Thalidomide, Bortezomib, and Lenalidomide on Myeloma Therapy
Although ASCT remains a critical treatment
option for appropriately selected MM patients, the introduction of thalidomide,
bortezomib, and lenalidomide in the past decade has dramatically altered the
overall therapeutic management of MM. Clinical trials comparing the historical
standard of care for upfront therapy in transplant-ineligible patients—
melphalan and prednisone (MP) — to MP in combination with either thalidomide5
or bortezomib6 showed superior overall and complete response rates, as well as
improved duration of response and overall survival. Likewise, preliminary
analysis of a phase III study comparing MP, MP plus lenalidomide, and MP plus
lenalidomide followed by lenalidomide maintenance demonstrated substantial
improvement in rates of overall and complete response as well as a significant
improvement in progression-free survival in the regimen that included
Thalidomide, bortezomib, and
lenalidomide also figure prominently in the treatment of newly diagnosed,
transplant- eligible MM patients. Whereas the combination of vincristine,
adriamycin, and dexamethasone formerly represented standard induction therapy
for such patients, the regimen has been supplanted on the basis of data from randomized
trials by thalidomide plus dexamethasone and by bortezomib plus dexamethasone.
Specifically, the majority of patients receiving these regimens achieve at
least a very good partial response after induction and a single ASCT, so that
fewer patients are candidates to benefit from a second transplant. Lenalidomide
plus low-dose dexamethasone is also well tolerated and active as induction
therapy in transplant-eligible patients.8 Bortezomib, lenalidomide, and/or
their combination are particularly attractive for patients with high-risk disease
based on staging criteria and cytogenetic abnormalities such as t(4;14) and
del(13), as several studies indicate that they may overcome the poor prognosis
associated with these genetic findings in relapsed disease.
|Click image to enlarge
The application of thalidomide,
bortezomib, and lenalidomide in MM therapy has been refined in recent years
through a series of important clinical investigations. Combinations of these
agents, such as bortezomib, thalidomide, and dexamethasone9 and lenalidomide,
bortezomib, dexamethasone,10 are being evaluated in newly diagnosed MM and have
proven to be very effective, yielding complete response rates approximating
those previously achieved with highdose therapy and ASCT. In addition, schedule
modifications have been introduced with the aim of minimizing toxicity while
preserving the activity of chemotherapeutic regimens. Finally, building on
previous studies of thalidomide maintenance therapy following ASCT, ongoing
clinical trials are evaluating lenalidomide and bortezomib consolidation and maintenance
following ASCT, and preliminary results suggest that increased extent of
response and prolonged progression-free survival can be achieved with these
agents, both as monotherapy and in combination. Figure 1 shows response rates
associated with various combination regimens.
Cell Transplantation in the New Era of Myeloma Therapy
In light of the fact that new
approaches to MM induction now produce a level of response previously seen only
with the incorporation of ASCT, it is critical for ASCT to be reevaluated in
the context of new induction and maintenance strategies. Questions of
significant interest and importance in the field include: Can highly active
induction regimens followed by maintenance therapy replace upfront ASCT for
patients who have been traditionally managed utilizing transplant? Conversely,
will such active induction regimens followed by ASCT, and thereafter by
maintenance, extend suppression of the myeloma clone beyond what has been
previously achieved, with resulting prolongation of progression-free and
overall survival? In addition, what is the optimal sequence of new induction
regimens and ASCT; should ASCT be performed immediately following induction therapy
or delayed until time of relapse?
|Click image to enlarge
A randomized, international clinical
trial developed by the Dana-Farber Cancer Institute and a consortium of U.S.
transplant centers working in partnership with the Inter-Groupe Francophone du
Myelome (IFM) has been designed to definitively address these issues (Figure
2). After receiving one cycle of induction with lenalidomide, bortezomib, and
dexamethasone, previously untreated MM patients will be randomized to receive
either: a) further induction with lenalidomide, bortezomib, and dexamethasone
followed by stem cell collection and ASCT, or b) further induction and stem
cell collection but no ASCT until time of relapse. Patients in both treatment
groups will receive consolidation with lenalidomide, bortezomib, and dexamethasone
and then lenalidomide maintenance for at least 12 months. It is anticipated
that results of this clinical trial will, together with other ongoing studies,
guide optimal timing and sequence of ASCT in the rapidly evolving field of MM
therapy, as well as provide insight on key surrogates and prognostic features,
such as cytogenetics and gene expression profiling. MM remains a formidable
adversary and must be countered with all available, active treatment modalities
in the most informed, coordinated manner possible to further improve patient
outcome, with the integration of novel therapies and ASCT offering a paradigm
for just such an approach.
- McElwain TJ, Powles RL. High-dose
intravenous melphalan for plasma-cell leukemia and myeloma. Lancet.
- Attal M, Harousseau JL, Stoppa AM, et al. A
prospective, randomized trial of autologous bone marrow transplantation and
chemotherapy in multiple myeloma. N Engl J Med. 1996;335:91-97.
- Attal M, Harousseau JL, Facon T, et al. Single
versus double autologous stem-cell transplantation for multiple myeloma. N
Engl J Med. 2003;349:2495-2502.
- Fermand JP, Katsahian S, Divine M, et al. High-dose
therapy and autologous blood stem-cell transplantation compared with
conventional treatment in myeloma patients aged 55 to 65 years: long-term
results of a randomized control trial from the Group Myelome-Autogreffe. J Clin Oncol. 2005;23:9227-33.
- Palumbo A, Bringhen S, Caravita T, et al. Oral
melphalan and prednisone chemotherapy plus thalidomide compared with melphalan
and prednisone alone in elderly patients with multiple myeloma: randomised
controlled trial. Lancet. 2006;367:825-31.
Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib
plus melphalan and prednisone for initial treatment of multiple myeloma. N
Engl J Med. 2008;359:906-17.
- Palumbo A, Dimopoulos MA, Delforge M, et al. A
phase III study to determine the efficacy and safety of lenalidomide in combination
with melphalan and prednisone (MPR) in elderly patients with newly diagnosed
multiple myeloma. Blood.
- Rajkumar SV, Jacobus S, Callander NS, et al. Lenalidomide
plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as
initial therapy for newly diagnosed multiple myeloma: an open-label randomised
controlled trial. Lancet Oncol. 2010;11:29-37.
- Cavo M, Tacchetti
P, Patriarca F, et al. Superior
complete response rate and progression-free survival after autologous
transplantation with up-front velcade-thalidomide-dexamethasone compared with
thalidomide-dexamethasone in newly diagnosed multiple myeloma. Blood.
PG, Lonial S, Jakubowiak AJ, et al. High
response rates and encouraging time-to-event data with lenalidomide,
bortezomib, and dexamethasone in newly diagnosed multiple myeloma: final
results of a phase I/II study. Blood. 2009;114:1218.
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